Cardioselectivity of the sulphonylurea HMR 1098:: studies on native and recombinant cardiac and pancreatic KATP channels

1 In this study we investigated the effects of the putative cardioselective sulphonylurea derivative HMR 1098 on ATP-sensitive potassium (K-ATP) channels from cardiac ventricular myocytes, the INS-1 beta-cell line and from recombinant K-ATP channels composed of SUR2A/Kir6.2, SUR1/Kir6.2, SUR1/Kir6.1 an Kir6.2,DeltaC26. Recombinant channels were expressed in tsA201 or COS-1 cells. 2 The effects of HMR 1098 on single channel and whole-cell currents were recorded using the patch-clamp technique. 3 At the single channel level, using excised inside-out membrane patches, HMR 1098 inhibited KATP channels from ventricular cells and INS-1 cells with IC(50)s of 0.88 and 720 muM respectively. Similar results to those in cardiac cells were obtained using recombinant SUR2A/Kir6.2 KATP channels. HMR 1098 inhibition of SUR2A/Kir6.2 KATP channels was unaffected by the presence of internal ADP. 4 In whole-cell recordings, HMR 1098 inhibited SUR2A/Kir6.2 and SUR1/-Kir6.2 currents with IC50S of 2.1 and 860 muM respectively. HMR 1098 was without effect on currents either from the Kir6.2,DeltaC26 truncation mutant or from Kir2.1. 5 Our results demonstrate that HMR 1098 is a selective inhibitor of cardiac KATP channels, showing a 400-800-fold selectivity over beta-cell KATP channels. The non-aromatic substitutions in the sulphonylurea moiety greatly increase the cardioselectivity of this compound while reducing the overall blocking potency of this sulphonylurea derivative.